In the yeast Saccharomyces cerevisiae, loss of the ARD1 (arrest-defective) gene leads to defects in cell cycle arrest (Whiteway, M. et al. (1985) Cell 43:483-492). Park, E. C. and Szostak, J. W. (1992; EMBO J. 11:2087-2093) subsequently demonstrated that ARD1 forms a complex with the protein NAT1 and that the complex displays N-terminal acetyl transferase activity. ARD1-NAT1 N-acetyl transferase activity is required for full repression of the silent mating type locus HML, for sporulation, and for entry into the stationary phase of the yeast cell cycle.
Protein acetylation is one of the most common post-translational protein modifications and appears to play a role in many biological processes. The most extensively studied acetylated proteins are the histones. Histones are nuclear proteins which bind DNA and are directly involved in both the packaging of DNA into chromosomes and in the regulation of transcription. Histones are subject to enzyme-catalyzed cycles of acetylation and deacetylation which affect chromatin structure, transcriptional activation, and cell cycle transit. Acetylated lysine residues in the NH.sub.2 -terminal region of the nucleosomal histones serve as landmarks for transcriptionally active chromatin within the chromosome.
Hyperacetylation of histones leads to conformational changes in nucleosome structure, destabilization of nucleosomal contacts, and an increase in the accessibility of nucleosomal DNA to transcription factors. Loss of histone acetylation is correlated with transcriptional silencing. Chromatin structure may be reversibly modulated to activate or silence transcription by targeting acetyl transferases or deacylases to a particular gene (Wolffe, A. P. (1996) Science 272:371-372).
Aberrant histone acetylation may contribute to a variety of human disorders related to cell cycle regulation. In addition, a close correlation was recently observed between the level of histone acetylation and expression of the HIV-1 provirus after its integration into the host cell genome (Van Lint, C. et al. (1996) EMBO J. 15:1112-1120).
The discovery of a new human N-acetyl transferase and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of disorders associated with cell proliferation and viral infection.